ABSTRACT Post-traumatic stress disorder (PTSD) is a debilitating and chronic mental illness with limited treatment options. Currently, there are only two FDA-approved PTSD medications both of which are monoaminergic antidepressants. Rates of non-response to these medications are high, in particular in military PTSD. Thus, we are proposing to examine the efficacy of a novel drug, ketamine, in treating antidepressant-resistant PTSD. Mounting evidence indicates that the N- methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, produces a rapid (within 4 hours) and potent (50% to 90% response rate) antidepressant action in patients with severe antidepressant-resistant depression. Pilot evidence and case reports provided preliminary evidence supporting the safety and utility of investigating the therapeutic effects of ketamine in PTSD. However, the efficacy of this drug has not yet been tested in an active duty military or veteran population with PTSD. As a project proposal to be funded under the DoD/VA collaborative Consortium to Alleviate PTSD (CAP), we propose a multisite, placebo-controlled, double blind clinical trial to examine the dose-related and multi-dose efficacy of ketamine, as compared to placebo, in producing a rapid and sustained reduction in PTSD and depressive symptomatology in an active duty military and veteran population with treatment-resistant PTSD. Approximately 198 eligible subjects who meet criteria for PTSD and additional inclusion and exclusion criteria will be randomized to the study drug (i.e. ketamine 0.5 mg/kg, ketamine 0.2 mg/kg, or placebo). The study drug will be administered intravenously twice per week for 4 weeks, followed by a 4-week follow-up period. The proposed 4-week repeat dosing study is, to our knowledge, the first test of the therapeutic effects of ketamine in the veteran population, and the first placebo-controlled multisite trial to determine the dose-related effects of repeated ketamine on PTSD. It will also be the largest ketamine clinical trial, which will provide critical information about the safety of repeated dosing and the durability of benefit following a 4-week treatment regimen approach. Blood collection and banking at the CAP Biomarkers and Genomics Core will be performed for future CAP spearheaded analyses.